Receptor tyrosine kinases play important roles in mediating the signal transduction and cellular communication process. Among the 58 receptor tyrosine kinases, only two are considered “orphan” kinases because their ligands have not been identified. ROS is one of the “orphan” tyrosine kinases.
Extensive research has been conducted to study the expression, effects, and localization of both ROS encoding genes and the various forms of ROS peptides. Several studies indicate that ROS are involved in the oncogenesis and tumor progression of various cancers. For example, overexpression of ROS cDNA and RNA was observed in surgical specimens in a significant proportion of glioblastoma samples. In addition, a large scale survey study revealed that in non-small cell lung cancer (NSCLC) tumors, ROS protein was highly expressed and the down stream effectors of ROS, such as insulin receptor substrate 2 (IRS-2), are highly phosphorylated, suggesting elevated ROS activities. Moreover, ROS up-regulation has been shown in gastric cancer model animals, liver cancer model animals, fibroadenoma tumor samples, colon adenocarcinoma cell lines, and a rat hepatoma cell line, indicating possibly extensive involvement of ROS in cancer development.
Aside from general over-expression, the ROS gene has also been shown to be rearranged in the form of fusion proteins in cancer-related samples. One key example is the “FIG-ROS” fusion in glioblastoma cells. Fused in Glioblastoma (FIG) is a gene that encodes a protein that peripherally associates with Giogi apparatus. The FIG-ROS kinase is encoded by 7 FIG-derived exons and 9 ROS-derived exons, a potent oncogene, capable of initiating malignant transformation in vitro when localized to the Golgi apparatus and activating growth signaling pathways. FIG-ROS is highly expressed in two glioblastoma cell lines (U-118MG and U-138 MG), suggesting that FIG-ROS is present in the primary tumors that established the two cell lines. Moreover, in a mouse model system, the FIG-ROS fusion cooperates with the loss of CDKN2A to produce glioblastoma. The involvement of CDKN2A is not surprising, given its classification as one of the most frequently deleted genes in glioblastoma. All these studies support the conclusion that ROS plays an important role in mediating cancer development.
In addition to the probable role in tumor formation and progression, ROS has been shown be involved in other illnesses such as cardiovascular diseases and male infertility. For example, a number of studies have correlated between the ROS gene and incidence of different cardiovascular diseases, such as myocardial infarction and hypertension. Similarly, male homozygous ROS knockout mice are infertile, with likely abnormal sperm development. These studies suggest that ROS may play important roles in diseases other than cancers.
Significant efforts have been focusing on generating ROS inhibitors that may help to provide a treatment cancer and other related diseases. A number of inhibitors, such as Staurosporine, AST-487 and PP 2 have been reported to inhibit ROS kinase activities. Among these, Staurosporine has shown a high potency with IC50 of 0.9 nM. These inhibitors, however, are highly unselective and their prospects of clinical application are probably minimum.
Following the finding of the non-specific ROS inhibitors, further studies discovered a new hit pyrazole derivative—KIST301072—that inhibits 94% of the ROS kinase activities at a concentration of 10 uM, while blocking less than 30% of the activities of other kinases at the same level. A dose response study showed that KIST301072 has an IC50 of about 199 nM. In addition, a structurally related compound, KIST301080 has been shown to inhibit ROS kinase activity with an IC50 of 209 nM. New studies will address the potential clinical applications of KIST301072 and KIST301080 in treating cancer, cardiovascular diseases, and infertility.
The current invention introduces a new set of compounds that selectively inhibits ROS kinase activities. These compounds may have significant pharmaceutical implications in the treatment of cancer, cardiovascular diseases, and infertility.